This proposal will address possible mechanisms for human CMV to cause atherosclerosis. The goal of this study is to examine the interaction of HCMV with host cells mediating vascular atherosclerosis. The ability of HCMV clinical isolates to cause infection in endothelial cells and induce cellular genes early in infection will be studied. The use of DNA array technology to study induction of human genes in vascular smooth muscle cells and infected endothelial cells will be employed. The hypothesis to be tested is that endothelial derived HCMV infection of vascular smooth muscle and endothelial cells can upregulate cellular gene expression. Cellular genes which enhance apoptosis or death ligands and enhance cellular proliferation will be initially measured. A murine model of atherosclerosis employing a strain of atherosclerosis prone mice infected with murine CMV will be developed. A pathological examination of the atherosclerosis induced in these mice will be performed. The CMV DNA copy number in atherosclerosis lesions will be correlated with the pathology of atherosclerosis. A trial of anti-CMV drugs will be employed to test that anti-CMV treatment will prevent development of athersclerosis. The specific aims for this proposal are :1. To determine the induction of human cellular gene expression by infection of smooth muscle cells by endothelial derived clinical isolates of HCMV. 2. To develop a model of murine CMV infection in mice to study vascular wall injury and the development of atherosclerosis. 3. To evaluate the role of specific treatment with anti CMV drugs in the development of endothelial damage in a murine model of atherosclerosis. This trial will include a novel inhibitor of HCMV primase. The overall goal of these studies is to identify the specific molecular interaction between HCMV gene products and human genes induced by HCMV which trigger the development of atherosclerosis.